O43889 · CREB3_HUMAN
- ProteinCyclic AMP-responsive element-binding protein 3
- GeneCREB3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids371 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription (PubMed:10984507, PubMed:15845366, PubMed:16940180, PubMed:19779205, PubMed:9271389).
Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death (PubMed:15845366, PubMed:16940180).
Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration (PubMed:15001559, PubMed:17296613, PubMed:19779205).
Associates with chromatin to the HERPUD1 promoter (PubMed:16940180).
Also induces transcriptional activation of chemokine receptors (PubMed:17296613, PubMed:18587271).
Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death (PubMed:15845366, PubMed:16940180).
Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration (PubMed:15001559, PubMed:17296613, PubMed:19779205).
Associates with chromatin to the HERPUD1 promoter (PubMed:16940180).
Also induces transcriptional activation of chemokine receptors (PubMed:17296613, PubMed:18587271).
(Microbial infection) Plays a role in human immunodeficiency virus type 1 (HIV-1) virus protein expression.
Isoform 1
(Microbial infection) May play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HCV) core protein.
Isoform 1
(Microbial infection) Plays a role in herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestering host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection.
Isoform 2
Functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Also decreases the acetylation level of histone H4. Does not promote the chemotactic activity of leukocyte cells.
Processed cyclic AMP-responsive element-binding protein 3
This is the transcriptionally active form that translocates to the nucleus and activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many promoters to activate transcription of the genes. Binds to the unfolded protein response element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3').
Processed cyclic AMP-responsive element-binding protein 3
(Microbial infection) Activates transcription of genes required for reactivation of the latent HSV-1 virus. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many viral promoters.
Processed cyclic AMP-responsive element-binding protein 3
(Microbial infection) It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator HCV core protein.
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 263-264 | Cleavage; by PS1 | ||||
Sequence: SR | ||||||
Site | 266-267 | Cleavage; by PS1 | ||||
Sequence: LR |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCyclic AMP-responsive element-binding protein 3
- Short namesCREB-3; cAMP-responsive element-binding protein 3
- Alternative names
- Cleaved into 1 chains
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO43889
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Isoform 1
Endoplasmic reticulum membrane ; Single-pass type II membrane protein
Isoform 1
Note: (Microbial infection) Sequestered into the cytoplasm by the HCV core protein.
Isoform 2
Processed cyclic AMP-responsive element-binding protein 3
Note: Upon RIP activation the transcriptional active processed cyclic AMP-responsive element-binding protein 3 form translocates into the nucleus. Detected in the nucleus upon dendritic cell maturation and RIP activation. Colocalizes with CREBRF in nuclear foci. Colocalizes with CREBZF in promyelocytic leukemia protein nuclear bodies (PML-NB).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-230 | Cytoplasmic | ||||
Sequence: MELELDAGDQDLLAFLLEESGDLGTAPDEAVRAPLDWALPLSEVPSDWEVDDLLCSLLSPPASLNILSSSNPCLVHHDHTYSLPRETVSMDLESESCRKEGTQMTPQHMEELAEQEIARLVLTDEEKSLLEKEGLILPETLPLTKTEEQILKRVRRKIRNKRSAQESRRKKKVYVGGLESRVLKYTAQNMELQNKVQLLEEQNLSLLDQLRKLQAMVIEISNKTSSSSTC | ||||||
Transmembrane | 231-247 | Helical; Signal-anchor for type II membrane protein | ||||
Sequence: ILVLLVSFCLLLVPAMY | ||||||
Topological domain | 248-371 | Lumenal | ||||
Sequence: SSDTRGSLPAEHGVLSRQLRALPSEDPYQLELPALQSEVPKDSTHQWLDGSDCVLQAPGNTSCLLHYMPQAPSAEPPLEWPFPDLFSEPLCRGPILPLQANLTRKGGWLPTGSPSVILQDRYSG |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 12-13 | Does not inhibit interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 56-A-A-57 and 78-A--A-81 (isoform 1). | ||||
Sequence: LL → AA | ||||||
Mutagenesis | 16-17 | Does not affect the transcriptional activation of the glucocorticoid receptor NR3C1; when associated with 57-A-A-58 (isoform 2). | ||||
Sequence: LL → AA | ||||||
Mutagenesis | 57-58 | Does not affect the transcriptional activation of the glucocorticoid receptor NR3C1; when associated with 16-A-A-17 (isoform 2). | ||||
Sequence: LL → AA | ||||||
Mutagenesis | 57-58 | Does not inhibit interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 12-A-A-13 and 78-A--A-81 (isoform 1). | ||||
Sequence: LL → AA | ||||||
Mutagenesis | 78-81 | Inhibits interaction with HCFC1. Reduces transcriptional activation. Inhibits strongly transcriptional activation; when associated with 12-A-A-13 and 56-A-A-57. Colocalizes with HCFC1 in the nucleus (isoform 1). | ||||
Sequence: DHTY → AAAA | ||||||
Mutagenesis | 81 | Does not retain HCFC1 in the cytoplasm, does not interact with HCFC1, does not activate promoter and fail to protect cells from a productive infection by HSV-1. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 160 | Does not bind to DNA but retains its ability to interact with HCFC1. Reduces transcriptional activation of unfolded protein response elements (UPRE)-containing promoter. Colocalizes with HCFC1 in the ER membrane. | ||||
Sequence: N → G | ||||||
Mutagenesis | 252 | Does not inhibit proteolytic cleavage and transcriptional activation. | ||||
Sequence: R → A | ||||||
Mutagenesis | 264 | Inhibits proteolytic cleavage and transcriptional activation. | ||||
Sequence: R → G | ||||||
Mutagenesis | 267 | Inhibits proteolytic cleavage and transcriptional activation. | ||||
Sequence: R → G |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 409 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000296204 | 1-? | Processed cyclic AMP-responsive element-binding protein 3 | |||
Chain | PRO_0000076602 | 1-371 | Cyclic AMP-responsive element-binding protein 3 | |||
Sequence: MELELDAGDQDLLAFLLEESGDLGTAPDEAVRAPLDWALPLSEVPSDWEVDDLLCSLLSPPASLNILSSSNPCLVHHDHTYSLPRETVSMDLESESCRKEGTQMTPQHMEELAEQEIARLVLTDEEKSLLEKEGLILPETLPLTKTEEQILKRVRRKIRNKRSAQESRRKKKVYVGGLESRVLKYTAQNMELQNKVQLLEEQNLSLLDQLRKLQAMVIEISNKTSSSSTCILVLLVSFCLLLVPAMYSSDTRGSLPAEHGVLSRQLRALPSEDPYQLELPALQSEVPKDSTHQWLDGSDCVLQAPGNTSCLLHYMPQAPSAEPPLEWPFPDLFSEPLCRGPILPLQANLTRKGGWLPTGSPSVILQDRYSG | ||||||
Glycosylation | 307 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 348 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Post-translational modification
First proteolytically cleaved by site-1 protease (S1P) that generates membrane-associated N-terminus and a luminal C-terminus forms. The membrane-associated N-terminus form is further proteolytically processed probably by the site-2 protease (S2P) through a regulated intramembrane proteolysis (RIP), releasing the transcriptional active processed cyclic AMP-responsive element-binding protein 3 form, which is transported to the nucleus. The proteolytic cleavage is strongly induced during dendritic cell (DC) maturation and inhibited by DCSTAMP. That form is rapidly degraded.
N-glycosylated.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Ubiquitously expressed (PubMed:19779205, PubMed:9271389).
Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level) (PubMed:20546900).
Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level) (PubMed:20546900).
Induction
Up-regulated upon differentiation of monocytes towards immature dendritic cells (DC). Down-regulated upon DC maturation. Up-regulated by endoplasmic reticulum stress triggered by thapsigargin (Tg) or tunicamycin (Tm). Up-regulated by CCR1-dependent chemokines in an immediate early response and biphasic manner and by NF-kappa-B.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homodimer (PubMed:10675342).
Isoform 1 interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity (PubMed:10629049, PubMed:10984507, PubMed:9271389, PubMed:9389645).
Isoform 1 interacts with CREBZF; the interaction occurs only in combination with HCFC1 (PubMed:15705566).
Isoform 1 interacts (via central part and transmembrane region) with DCSTAMP (via C-terminus cytoplasmic domain) (PubMed:20546900).
Isoform 1 interacts with OS9 (PubMed:20546900).
Isoform 1 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation (PubMed:18391022).
Isoform 1 interacts (via C-terminal domain) with CCR1 (PubMed:15001559).
Isoform 1 interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity (PubMed:10629049, PubMed:10984507, PubMed:9271389, PubMed:9389645).
Isoform 1 interacts with CREBZF; the interaction occurs only in combination with HCFC1 (PubMed:15705566).
Isoform 1 interacts (via central part and transmembrane region) with DCSTAMP (via C-terminus cytoplasmic domain) (PubMed:20546900).
Isoform 1 interacts with OS9 (PubMed:20546900).
Isoform 1 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation (PubMed:18391022).
Isoform 1 interacts (via C-terminal domain) with CCR1 (PubMed:15001559).
(Microbial infection) Interacts with the HCV core protein; homodimerization is prevented by the HCV core protein (PubMed:10675342).
Isoform 1 interacts (via leucine-zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability (PubMed:17054986).
Processed cyclic AMP-responsive element-binding protein 3 interacts with HIV-1 Tat (PubMed:17054986).
Isoform 1 interacts (via leucine-zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability (PubMed:17054986).
Processed cyclic AMP-responsive element-binding protein 3 interacts with HIV-1 Tat (PubMed:17054986).
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, motif, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-92 | Transcription activation (acidic) | ||||
Sequence: MELELDAGDQDLLAFLLEESGDLGTAPDEAVRAPLDWALPLSEVPSDWEVDDLLCSLLSPPASLNILSSSNPCLVHHDHTYSLPRETVSMDL | ||||||
Motif | 13-17 | LXXLL motif 1 | ||||
Sequence: LAFLL | ||||||
Motif | 54-58 | LXXLL motif 2 | ||||
Sequence: LCSLL | ||||||
Motif | 78-81 | HCFC1-binding-motif (HBM) | ||||
Sequence: DHTY | ||||||
Domain | 150-213 | bZIP | ||||
Sequence: ILKRVRRKIRNKRSAQESRRKKKVYVGGLESRVLKYTAQNMELQNKVQLLEEQNLSLLDQLRKL | ||||||
Region | 152-184 | Basic motif | ||||
Sequence: KRVRRKIRNKRSAQESRRKKKVYVGGLESRVLK | ||||||
Region | 192-213 | Leucine-zipper | ||||
Sequence: LQNKVQLLEEQNLSLLDQLRKL |
Sequence similarities
Belongs to the bZIP family. ATF subfamily.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
O43889-2
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- SynonymsLZIP
- Length371
- Mass (Da)41,379
- Last updated2018-03-28 v2
- Checksum82152E496B924EEC
O43889-3
- Name2
- Synonymssmall LZIP, sLZIP
- NoteDoes not contain a helical transmembrane domain.
- Differences from canonical
- 229-245: Missing
Sequence caution
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 21 | in Ref. 6; AAG43527 | ||||
Sequence: G → E | ||||||
Alternative sequence | VSP_059386 | 229-245 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 230 | in Ref. 3; AAD09210 | ||||
Sequence: C → G | ||||||
Sequence conflict | 246 | in Ref. 8; AAH09402 | ||||
Sequence: M → I | ||||||
Sequence conflict | 262 | in Ref. 3; AAD09210 | ||||
Sequence: L → C | ||||||
Sequence conflict | 333 | in Ref. 1; AAB69652 | ||||
Sequence: F → S | ||||||
Sequence conflict | 338 | in Ref. 3; AAD09210 | ||||
Sequence: C → V |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF009368 EMBL· GenBank· DDBJ | AAB69652.1 EMBL· GenBank· DDBJ | mRNA | ||
AF029674 EMBL· GenBank· DDBJ | AAB84166.1 EMBL· GenBank· DDBJ | mRNA | ||
U59629 EMBL· GenBank· DDBJ | AAD09210.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
FJ263669 EMBL· GenBank· DDBJ | ACN32251.1 EMBL· GenBank· DDBJ | mRNA | ||
U88528 EMBL· GenBank· DDBJ | AAC04325.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
AF211847 EMBL· GenBank· DDBJ | AAG43527.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF211848 EMBL· GenBank· DDBJ | AAG43528.1 EMBL· GenBank· DDBJ | mRNA | ||
AL133410 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC009402 EMBL· GenBank· DDBJ | AAH09402.1 EMBL· GenBank· DDBJ | mRNA | ||
BC010158 EMBL· GenBank· DDBJ | AAH10158.1 EMBL· GenBank· DDBJ | mRNA |